The present invention relates to a process for producing a 25 alkylidene-4-bromoacetoacetic acid ester that is useful as an intermediate of pharmaceuticals, specifically, as an intermediate of a side chain part of antibiotics disclosed in Japanese Patent No. 2618119.
In the Japanese Patent No. 2618119 there is disclosed a process for producing a 2-alkylidene-4-bromoacetoacetic acid ester in which process methyl 2-propylidene-4-chloroacetoacetate is subjected to a halogen exchange reaction with sodium bromide, wherein said methyl 2-propylidene-4-chloroacetoacetate was obtained by condensing methyl 4-chloroacetoacetate and propionaldehyde by using piperidine and acetic acid as catalysts.
This process, however, is not always satisfactory in that it requires a halogen exchange reaction wherein the conversion ratio is not satisfactory and expensive methyl 4-chloroacetoacetate is required. Hence, new production processes have been desired.
An object of the Invention is to provide a process which can provide the desired 2-alkylidene-4-bromoacetoacetic acid ester by using, as a starting material, a 4-bromoacetoacetic acid ester which can be readily derived from an acetoacetic acid ester in a good yield in an industrial scale.
The present invention provides:
a process for producing a 2-alkylidene-4-bromoacetoacetic acid ester of the formula (3): 
xe2x80x83wherein R1 and R2 each independently represent a lower alkyl group having 1-5 carbon atoms, which comprises:
reacting a 4-bromoacetoacetic acid ester of the formula (1): 
wherein R1 has the same meaning as defined above, with an aldehyde of the formula (2):
R2CHOxe2x80x83xe2x80x83(2)
wherein R2 has the same meaning as defined above, in an inert organic solvent in the presence of an amine and a carboxylic acid.
The 4-bromoacetoacetic acid ester of the formula (1) used in the present invention, can be readily prepared by reacting an acetoacetic acid ester of the formula (4): 
wherein R1 has the same meaning as defined above, with bromine in the presence of an organic solvent according to the method disclosed in J. Org. Chem., 12, 342 (1947), Helvetica Chemica Acta, 66, 1475 (1983), or the like.
Although the 4-bromoacetoacetic acid ester prepared in the above-described method may be used as a starting material in the present invention after being purified by distillation or the like, a concentrated reaction mixture obtained by a partial or total evaporation of the solvent from the reaction mixture may be used as it is without purification.
Examples of the lower alkyl group having 1 to 5 carbon atoms for R1 in the 4-bromoacetoacetic acid ester of the formula (1) include a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a t-butyl group and a n-pentyl group
Specific examples of the 4-bromoacetoacetic acid ester of the formula (1) include methyl 4-bromoacetoacetate, ethyl 4-bromoacetoacetate, n-propyl 4-bromoacetoacetate, i-propyl 4-bromoacetoacetate, n-butyl 4-bromoacetoacetate, t-butyl 4-bromoacetoacetate, n-pentyl 4-bromoacetoacetate, and the like.
Examples of the lower alkyl group having 1 to 5 carbon atoms for R2 in the aldehyde of the formula (2) in the present invention include a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a t-butyl group and a n-pentyl group.
Specific examples of the aldehyde of the formula (2) include acetaldehyde, propionaldehyde, butylaldehyde, isobutylaldehyde, valeraldehyde, trimethylacetaldehyde, hexanal, and the like.
The amount of the aldehyde to be used of the formula (2) is usually 1 to 10 moles, preferably 1.2 to 5 moles per mol of the 4-bromoacetoacetic acid ester of the formula (1).
The reaction of the present invention is carried out in the presence of an amine and a carboxylic acid as catalysts. Specific examples of the amine include:
primary amines, for example, ammonia, a (C1-C20)alkylamine (e.g., methylamine, ethylamine and n-propylamine),
secondary amines, for example, a di(C1-C20)alkylamine, which alkyl may be the same or different and may contain a heteroatom such as oxygen or nitrogen(e.g., dimethylamine, diethylamine, piperidine and morpholine), tertiary amines, for example, a tri(C1-C20)alkylamine, which alkyl may be the same or different, (e.g., triethylamine) and a (C5-C9)aromatic tertiary amine (e.g., pyridine) and mixtures thereof. The secondary amines are preferably used.
Specific examples of the carboxylic acid include a (C2-C6)alkanoic acid such as acetic acid, propionic acid, butyric acid, valeric acid, caproic acid and mixtures thereof.
The amount of the amine to be used is usually 0.001 to 1 mole, preferably 0.01 to 0.5 mol per mol of the 4-bromoacetoacetic acid ester of the formula (1).
The amount of the carboxylic acid to be used is usually 0.1 to 10 moles, preferably 0.5 to 5 moles per mol of the amine.
The reaction is usually carried out in an inert organic solvent. Such an inert organic solvent is not particularly limited unless it affects the reaction adversely. Specific examples thereof include aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, 1-chlorobutane and chlorobenzene, ethers such as diethyl ether, t-butyl methyl ether and tetrahydrofuran, ketones such as methyl ethyl ketone and methyl isobutyl ketone, etc.
These organic solvents may be used alone or as a mixture of two or more of them. The amount of the inert organic solvent to be used is not particularly limited and is usually in 0.5 to 100 parts, preferably 1 to 30 parts per 1 part by weight of the 4-bromoacetoacetic acid ester of the formula (1).
The reaction temperature is usually in the range of xe2x88x9280 to 30xc2x0 C., preferably in the range of xe2x88x9250 to 0xc2x0 C.
The way to feed the starting materials and catalysts for the reaction is important in order to control side reactions such as self-condensation of the aldehyde of the formula (2), and the like and to achieve good yield.
The reaction can usually be conducted by adding the amine to a solution of the 4-bromoacetoacetic acid ester of the formula (1), the aldehyde of the formula (2) and the carboxylic acid in an inert organic solvent.
Alternatively it may be preferably conducted in the following manner which advantageously facilitates the control of the reaction temperature of the exothermic reaction from industrial viewpoint:
the reaction can be conducted by adding in parallel the 4-bromoacetoacetic acid ester of the general formula (1), the aldehyde of the formula (2) and the amine to a solution of the carboxylic acid catalyst in the inert organic solvent; or
the reaction is conducted by adding the 4-bromoacetoacetic acid ester of the formula (1), the aldehyde of the formula (2), the amine and carboxylic acid in parallel to an inert organic solvent.
After completion of the reaction, the reaction mixture is, for example, washed with an aqueous acid solution, water and the like and the solvent is concentrated to give the desired 2-alkylidene-4-bromoacetoacetic acid ester of the formula (3). The solution of 2-alkylidene-4-bromoacetoacetic acid ester of the formula (3) after washing is preferably used as it is.
According to the process of the present invention, a 2-alkylidene-4-bromoacetoacetic acid ester that is useful as intermediates of pharmaceuticals and the like can be produced in good yield and advantageously from industrial view point.